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Usefulness of International Normalized Ratio to Predict Bleeding Complications in Patients With End-Stage Liver Disease Who Undergo Cardiac Catheterization
Usefulness of International Normalized Ratio to Predict Bleeding Complications in Patients With End-Stage Liver Disease Who Undergo Cardiac Catheterization Jacob C. Townsend, MDa,*, Richard Heard, MDb, Eric R. Powers, MDa, and Adrian Reuben, MBBSc Patients with end-stage liver disease frequently require invasive cardiac procedures in preparation for liver transplantation. Because of the impaired hepatic function, these patients often have a prolonged prothrombin time and elevated international normalized ratio (INR). To determine whether an abnormal prothrombin time/INR is predictive of bleeding complications from invasive cardiac procedures, we retrospectively reviewed, for bleeding complications, the databases and case records of our series of patients with advanced cirrhosis who underwent cardiac catheterization. A total of 157 patients underwent isolated right-sided heart catheterization, and 83 underwent left-sided heart catheterization or combined left- and right-sided heart catheterization. The INR ranged from 0.93 to 2.35. No major procedure-related complications occurred. Several patients in each group required a blood transfusion for gastrointestinal bleeding but not for procedurerelated bleeding. No significant change was found in the hemoglobin after right-sided or left-sided heart catheterization, and no correlation was found between the preprocedure INR and the change in postprocedure hemoglobin. When comparing patients with a normal (<1.5) and elevated (>1.5) INR, no significant difference in hemoglobin after the procedure was found in either group. In conclusion, despite an elevated INR, patients with end-stage liver disease can safely undergo invasive cardiac procedures. An elevated INR does not predict catheterization-related bleeding complications in this patient population. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110: 1062–1065) At present, few published data are available regarding the bleeding risk from cardiac procedures in patients with end-stage liver disease (ESLD). Three single-center studies have been published comparing patients with ESLD to matched cohorts and have found a similar to slightly greater procedure-related complication rate in those with ESLD.1–3 Of particular interest were the findings that the preprocedure international normalized ratio (INR) was associated with bleeding risk3 and, in a second study, that the treatment of an INR ⬎1.6 with fresh frozen plasma (FFP) might have a reduced bleeding risk.2 Therefore, we sought to determine whether an elevated INR is predictive of complications from cardiac catheterization in patients with ESLD.
Divisions of aCardiology and cGastroenterology and Hepatology, bDepartment of Medicine, Medical University of South Carolina, Charleston, South Carolina. Manuscript received April 9, 2012; revised manuscript received and accepted May 9, 2012. This publication was supported by the South Carolina Clinical and Translational Research Institute, Medical University of South Carolina’s Clinical and Translational Science Awards Consortium, and grant UL1RR029882 from the National Institutes of Health/National Center Research Resources (Bethesda, Maryland). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or National Center Research Resources. *Corresponding author: Tel: (843) 876-4809; fax: (843) 876-4809. E-mail address: [email protected] (J.C. Townsend). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.05.043
Methods After approval by the Medical University of South Carolina institutional review board, we searched our liver transplant and heart catheterization databases for patients undergoing invasive cardiac procedures from May 2003 to August 2009. The patients were divided into those undergoing isolated right-sided heart catheterization (RHC) or left-sided heart catheterization (LHC); the latter group included those undergoing LHC with or without associated RHC. We collected the demographic, laboratory, and procedural data for each patient. The model for end-stage liver disease scores and body mass index were calculated for each patient.4 Venous access in the isolated RHC group was predominately in an internal jugular vein (90 of 157, 57%) with the remainder femoral. A 7F sheath was used most often (139 of 157, 89%). Most patients with combined RHC and LHC had femoral venous access (58 of 66, 89%) with a 7F sheath (65 of 66, 98%). Arterial access was uniformly in a femoral artery, with 4F (40 of 83, 48%) and 6F (34 of 83, 41%) sheaths used most commonly. Neither ultrasound guidance nor micropuncture technique was routinely used during the study period. The daily notes and radiology reports were searched for any evidence of vascular complications or significant bleeding at the catheterization sites or elsewhere. We specifically searched for the development of arteriovenous fistulas, aneurysms or pseudoaneurysms, evidence of retroperitoneal www.ajconline.org
Miscellaneous/Cardiac Catheterization in Patients With Coagulopathy
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Table 1 Demographic, laboratory, and procedural data Variable
Age (years) Men White Weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg Hemoglobin (g/dl) Platelets (ml) Creatinine (mg/dl) Model for end-stage liver disease International normalized ratio Concurrent right-sided heart catheterization
RHC (n ⫽ 157)
p Value
INR ⱕ1.5 61%
INR ⬎1.5 39%
55 ⫾ 7.9 57% 79% 90 ⫾ 22 31 ⫾ 7 125 ⫾ 21 72 ⫾ 12 12 ⫾ 2.0 101 ⫾ 57 1.35 ⫾ 1.0 13 ⫾ 5.3 1.3 ⫾ 0.14
52 ⫾ 10 62% 89% 89 ⫾ 22 29 ⫾ 6 121 ⫾ 18 67 ⫾ 13 10 ⫾ 2.1 105 ⫾ 102 1.57 ⫾ 1.7 21 ⫾ 7.4 1.8 ⫾ 0.21
0.07 0.84 0.65 0.76 0.24 0.24 0.01 ⬍0.01 0.79 0.31 ⬍0.01 ⬍0.01
LHC (n ⫽ 83) INR ⱕ1.5 72%
INR ⬎1.5 28%
57 ⫾ 9.2 73% 78% 93 ⫾ 17 31 ⫾ 5 122 ⫾ 23 65 ⫾ 13 12 ⫾ 2.1 97 ⫾ 53 1.49 ⫾ 1.2 14 ⫾ 6.4 1.25 ⫾ 0.14 75% (45)
52 ⫾ 7.8 61% 91% 90 ⫾ 25 30 ⫾ 7.3 121 ⫾ 21 64 ⫾ 14 10 ⫾ 1.9 77 ⫾ 32 1.58 ⫾ 1.2 22 ⫾ 6.4 1.74 ⫾ 0.18 91% (21)
p Value
0.02 0.78 0.81 0.52 0.62 0.91 0.76 ⬍0.01 0.1 0.76 ⬍0.01 ⬍0.01 0.12
Figure 1. Pre- to postprocedure changes in hemoglobin are plotted on the vertical axis against INR on the horizontal axis for patients undergoing isolated RHC (A) and LHC (B). Bold middle line indicates the median, top and bottom lines of box, 25th and 75th percentiles, and whiskers 1.5 multiplied by the interquartile range.
bleeding, hematomas, or intracranial bleeding. Outpatients with an uncomplicated course were discharged after the procedure, and, as a result, follow-up laboratory data were only available for 62% of the isolated RHC and 70% of the LHC group. The administration of platelets and FFP within 24 hours of the procedure was also recorded, as well as red blood cell infusion at any point afterward. The decision to transfuse FFP or platelets was at the discretion of the cardiologist performing the procedure. Statistical analysis was performed with Spearman’s rank correlation coefficient to search for a relationship between INR and postprocedural hemoglobin changes. Postprocedural differences in hemoglobin were also compared between subgroups with a normal (ⱕ1.5) and elevated (⬎1.5) INR, using Student’s t test. A p value ⬍0.05 was considered statistically significant. Results A total of 157 patients had undergone isolated RHC and 83 had undergone LHC, of whom a large majority (66 of 83)
had undergone associated RHC. The mean INR in the patients undergoing isolated RHC was 1.5 ⫾ 0.3 (range 0.93 to 2.35). In the LHC group, the mean INR was 1.38 ⫾ 0.3 (range 0.94 to 2.15). The demographic, laboratory, and procedural data are listed in Table 1. No major vascular complications or procedure-related bleeding events were identified in any patient. Of those with complete laboratory data, no significant difference was seen between the pre- and postprocedure hemoglobin in the isolated RHC (10.5 vs 10.5 g/dl, p ⫽ 0.83) or LHC (11.1 vs 11 g/dl, p ⫽ 0.83) group. In patients with isolated RHC, no significant change was seen in hemoglobin in either the normal or elevated INR groups (9.7 vs 9.7 g/dl, p ⫽ 0.98, and 11.1 vs 10.9 g/dl, p ⫽ 0.1, respectively). Similarly, in the LHC group, no significant change in hemoglobin was found in the normal or elevated INR group (9.5 vs 9.6 g/dl, p ⫽ 0.87, and 9.7 vs 9.7 g/dl, p ⫽ 0.99, respectively; Figure 1). To search for a relationship between the postprocedure changes in hemoglobin and INR, the corresponding values were plotted, but no correlation was seen in either the RHC ( ⫽
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The American Journal of Cardiology (www.ajconline.org)
Figure 2. Scatter plots of the change in hemoglobin before and after catheterization versus preprocedure INR. No correlation between change in hemoglobin and INR was identifiable in either isolated RHC (A) or LHC (B) group.
0.1176; p ⫽ 0.248) or LHC ( ⫽ ⫺0.0463; p ⫽ 0.820) group (Figure 2). Of the 157 patients who underwent isolated RHC, 11 received FFP before the procedure. The mean INR in these patients was 2.4 (range 1.9 to 3.3). Despite transfusion of ⱖ2 U of FFP, only 1 patient had their INR decrease to ⬍1.9. Two patients with a platelet count ⬍50,000/mm3 received platelet transfusions. Finally, 3 patients received packed red blood cells. In 2 of these cases, gastrointestinal bleeding caused anemia; in the third, the decrease in hemoglobin was attributed to hemodilution because no overt or concealed bleeding was found. Of the 83 patients in the LHC group, 6 received preprocedure FFP. The mean INR in these patients was 2.3 (range 1.9 to 3.3). After transfusion, the INR decreased to ⬍1.5 in only 1 patient. Four patients with a platelet count ⬍40,000/ mm3 received platelet transfusions. Three patients received a packed red blood cell infusion. In each case, the anemia was attributed to gastrointestinal bleeding. Discussion In the present study, we sought to find an association between INR and bleeding associated with cardiac catheterization in patients with ELSD and found none. Our data suggest that a moderately elevated INR poses no risk with invasive procedures in patients with ESLD despite the concern frequently expressed by those who perform such procedures. Even when our patients were dichotomized into normal and elevated INR groups, no significant difference in procedural complications was identified. This is especially important because one of the greatest reported reasons for blood product administration is the correction of an elevated INR in preparation for an invasive procedure.5 Historically, an elevated prothrombin time and its derived INR have been used to predict bleeding from invasive procedures. Although these laboratory variables are associated with an increased risk of hemorrhage in patients treated with warfarin-type anticoagulants, their utility and ability to predict bleeding in patients with cirrhosis is unclear.6,7 Patients with ESLD, because of their impaired hepatic syn-
thetic function, have a characteristic coagulation profile that is now referred to as “rebalanced hemostasis.”8 Hepatic production of both procoagulant (factors II, VII, IX, X) and anticoagulant (protein C, protein S, antithrombin) factors is reduced.7 This resets the hemostatic balance despite an increase in the prothrombin time/INR. Continued understanding of the complex interplay between those factors that promote and those that impair hemostasis has cast doubt on whether the prothrombin time/INR is predictive of bleeding risk in patients with ESLD or merely serves as a marker of hepatic synthetic impairment.7 Our findings are in accordance with the results of several published studies.9 Segal and Dzik,10 in a large systematic review of studies involving patients with an elevated prothrombin time or INR, did not find a significant increase in bleeding, although not all the studies they reviewed included patients with ESLD. One study included in their review is worth highlighting. In that prospective investigation of patients with ESLD undergoing central venous access placement, only 1 major bleeding complication was observed, and this was in a patient with an INR of 1.5. When comparing patients with an INR ⬎5 and ⬍5, the only statistically significant different finding was for superficial hematomas, which were found in 12.4% of those with an INR ⬎5 and in only 5.6% of those with an INR ⬍5.11 Not only do these published results suggest that the INR might not accurately predict those at high risk of bleeding, but also little evidence is available to suggest that the correction of INR by administration of FFP has any beneficial clinical effect.12,13 Thus, the potential risk and significant cost associated with blood product transfusion could be avoided in this patient population. Bleeding complications with invasive procedures can still occur in patients with ESLD—just as they can in patients without ESLD— but when they do, the INR elevation is not likely to be the cause. Several limitations were inherent to our retrospective study in which only major bleeding and vascular events were likely to have been recorded, and small hematomas or increased bruising might have been missed or not consid-
Miscellaneous/Cardiac Catheterization in Patients With Coagulopathy
ered clinically significant enough to have been reported. Undoubtedly, the possibility of selection bias was present such that those considered most at risk of procedural complications did not undergo catheterization. It could also be that the operating physicians, aware of the elevated INR levels, took extra care to avoid bleeding complications. Despite a patient population with an elevated INR, high model for ESLD scores, renal dysfunction, and thrombocytopenia, we did not identify any serious catheter-related complications, nor could we find any association between INR and bleeding risk. Our conclusion, inferred from the present findings and the results of published studies, is that the correction of INR with FFP, which puts the patients at risk of volume overload and transfusion-related acute lung injury,14 to reduce a theoretical risk of catheterization-related bleeding owing to INR elevation, is unnecessary. These results should be confirmed prospectively and include patients with ESLD and greater INR levels than seen in our population. 1. Vaitkus PT, Dickens C, McGrath MK. Low bleeding risk from cardiac catheterization in patients with advanced liver disease. Catheter Cardiovasc Interv 2005;65:510 –512. 2. Pillarisetti J, Patel P, Duthuluru S, Roberts J, Chen W, Genton R, Wiley M, Candipan R, Tadros P, Gupta K. Cardiac catheterization in patients with end-stage liver disease: safety and outcomes. Catheter Cardiovasc Interv 2011;77:45– 48. 3. Sharma M, Yong C, Majure D, Zellner C, Roberts JP, Bass NM, Ports TA, Yeghiazarians Y, Gregoratos G, Boyle AJ. Safety of cardiac catheterization in patients with end-stage liver disease awaiting liver transplantation. Am J Cardiol 2009;103:742–746. 4. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing tran-
5. 6.
7. 8. 9.
10.
11.
12.
13.
14.
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sjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864 – 871. Dzik W, Rao A. Why do physicians request fresh frozen plasma? Transfusion 2004;44:1393–1394. Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association, American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692–1711. Roberts LN, Patel RK, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol 2010;148:507–521. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010;116:878 – 885. Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis RB, Postoak DW, Rajan DK, Sacks D, Schwartzberg MS, Zuckerman DA, Cardella JF; Standards of Practice Committee with Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol 2009;20:S240 –S249. Segal JB, Dzik WH; Transfusion Medicine/Hemostasis Clinical Trials Network. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005;45:1413–1425. Fisher NC, Mutimer DJ. Central venous cannulation in patients with liver disease and coagulopathy—a prospective audit. Intensive Care Med 1999;25:481– 485. Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol 2003;98:1391–1394. Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;126:139 –152. Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore SB, Hubmayr RD, Gajic O. Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007;131:1308 –1314.
Divisions of aCardiology and cGastroenterology and Hepatology, bDepartment of Medicine, Medical University of South Carolina, Charleston, South Carolina. Manuscript received April 9, 2012; revised manuscript received and accepted May 9, 2012. This publication was supported by the South Carolina Clinical and Translational Research Institute, Medical University of South Carolina’s Clinical and Translational Science Awards Consortium, and grant UL1RR029882 from the National Institutes of Health/National Center Research Resources (Bethesda, Maryland). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or National Center Research Resources. *Corresponding author: Tel: (843) 876-4809; fax: (843) 876-4809. E-mail address: [email protected] (J.C. Townsend). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.05.043
Methods After approval by the Medical University of South Carolina institutional review board, we searched our liver transplant and heart catheterization databases for patients undergoing invasive cardiac procedures from May 2003 to August 2009. The patients were divided into those undergoing isolated right-sided heart catheterization (RHC) or left-sided heart catheterization (LHC); the latter group included those undergoing LHC with or without associated RHC. We collected the demographic, laboratory, and procedural data for each patient. The model for end-stage liver disease scores and body mass index were calculated for each patient.4 Venous access in the isolated RHC group was predominately in an internal jugular vein (90 of 157, 57%) with the remainder femoral. A 7F sheath was used most often (139 of 157, 89%). Most patients with combined RHC and LHC had femoral venous access (58 of 66, 89%) with a 7F sheath (65 of 66, 98%). Arterial access was uniformly in a femoral artery, with 4F (40 of 83, 48%) and 6F (34 of 83, 41%) sheaths used most commonly. Neither ultrasound guidance nor micropuncture technique was routinely used during the study period. The daily notes and radiology reports were searched for any evidence of vascular complications or significant bleeding at the catheterization sites or elsewhere. We specifically searched for the development of arteriovenous fistulas, aneurysms or pseudoaneurysms, evidence of retroperitoneal www.ajconline.org
Miscellaneous/Cardiac Catheterization in Patients With Coagulopathy
1063
Table 1 Demographic, laboratory, and procedural data Variable
Age (years) Men White Weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg Hemoglobin (g/dl) Platelets (ml) Creatinine (mg/dl) Model for end-stage liver disease International normalized ratio Concurrent right-sided heart catheterization
RHC (n ⫽ 157)
p Value
INR ⱕ1.5 61%
INR ⬎1.5 39%
55 ⫾ 7.9 57% 79% 90 ⫾ 22 31 ⫾ 7 125 ⫾ 21 72 ⫾ 12 12 ⫾ 2.0 101 ⫾ 57 1.35 ⫾ 1.0 13 ⫾ 5.3 1.3 ⫾ 0.14
52 ⫾ 10 62% 89% 89 ⫾ 22 29 ⫾ 6 121 ⫾ 18 67 ⫾ 13 10 ⫾ 2.1 105 ⫾ 102 1.57 ⫾ 1.7 21 ⫾ 7.4 1.8 ⫾ 0.21
0.07 0.84 0.65 0.76 0.24 0.24 0.01 ⬍0.01 0.79 0.31 ⬍0.01 ⬍0.01
LHC (n ⫽ 83) INR ⱕ1.5 72%
INR ⬎1.5 28%
57 ⫾ 9.2 73% 78% 93 ⫾ 17 31 ⫾ 5 122 ⫾ 23 65 ⫾ 13 12 ⫾ 2.1 97 ⫾ 53 1.49 ⫾ 1.2 14 ⫾ 6.4 1.25 ⫾ 0.14 75% (45)
52 ⫾ 7.8 61% 91% 90 ⫾ 25 30 ⫾ 7.3 121 ⫾ 21 64 ⫾ 14 10 ⫾ 1.9 77 ⫾ 32 1.58 ⫾ 1.2 22 ⫾ 6.4 1.74 ⫾ 0.18 91% (21)
p Value
0.02 0.78 0.81 0.52 0.62 0.91 0.76 ⬍0.01 0.1 0.76 ⬍0.01 ⬍0.01 0.12
Figure 1. Pre- to postprocedure changes in hemoglobin are plotted on the vertical axis against INR on the horizontal axis for patients undergoing isolated RHC (A) and LHC (B). Bold middle line indicates the median, top and bottom lines of box, 25th and 75th percentiles, and whiskers 1.5 multiplied by the interquartile range.
bleeding, hematomas, or intracranial bleeding. Outpatients with an uncomplicated course were discharged after the procedure, and, as a result, follow-up laboratory data were only available for 62% of the isolated RHC and 70% of the LHC group. The administration of platelets and FFP within 24 hours of the procedure was also recorded, as well as red blood cell infusion at any point afterward. The decision to transfuse FFP or platelets was at the discretion of the cardiologist performing the procedure. Statistical analysis was performed with Spearman’s rank correlation coefficient to search for a relationship between INR and postprocedural hemoglobin changes. Postprocedural differences in hemoglobin were also compared between subgroups with a normal (ⱕ1.5) and elevated (⬎1.5) INR, using Student’s t test. A p value ⬍0.05 was considered statistically significant. Results A total of 157 patients had undergone isolated RHC and 83 had undergone LHC, of whom a large majority (66 of 83)
had undergone associated RHC. The mean INR in the patients undergoing isolated RHC was 1.5 ⫾ 0.3 (range 0.93 to 2.35). In the LHC group, the mean INR was 1.38 ⫾ 0.3 (range 0.94 to 2.15). The demographic, laboratory, and procedural data are listed in Table 1. No major vascular complications or procedure-related bleeding events were identified in any patient. Of those with complete laboratory data, no significant difference was seen between the pre- and postprocedure hemoglobin in the isolated RHC (10.5 vs 10.5 g/dl, p ⫽ 0.83) or LHC (11.1 vs 11 g/dl, p ⫽ 0.83) group. In patients with isolated RHC, no significant change was seen in hemoglobin in either the normal or elevated INR groups (9.7 vs 9.7 g/dl, p ⫽ 0.98, and 11.1 vs 10.9 g/dl, p ⫽ 0.1, respectively). Similarly, in the LHC group, no significant change in hemoglobin was found in the normal or elevated INR group (9.5 vs 9.6 g/dl, p ⫽ 0.87, and 9.7 vs 9.7 g/dl, p ⫽ 0.99, respectively; Figure 1). To search for a relationship between the postprocedure changes in hemoglobin and INR, the corresponding values were plotted, but no correlation was seen in either the RHC ( ⫽
1064
The American Journal of Cardiology (www.ajconline.org)
Figure 2. Scatter plots of the change in hemoglobin before and after catheterization versus preprocedure INR. No correlation between change in hemoglobin and INR was identifiable in either isolated RHC (A) or LHC (B) group.
0.1176; p ⫽ 0.248) or LHC ( ⫽ ⫺0.0463; p ⫽ 0.820) group (Figure 2). Of the 157 patients who underwent isolated RHC, 11 received FFP before the procedure. The mean INR in these patients was 2.4 (range 1.9 to 3.3). Despite transfusion of ⱖ2 U of FFP, only 1 patient had their INR decrease to ⬍1.9. Two patients with a platelet count ⬍50,000/mm3 received platelet transfusions. Finally, 3 patients received packed red blood cells. In 2 of these cases, gastrointestinal bleeding caused anemia; in the third, the decrease in hemoglobin was attributed to hemodilution because no overt or concealed bleeding was found. Of the 83 patients in the LHC group, 6 received preprocedure FFP. The mean INR in these patients was 2.3 (range 1.9 to 3.3). After transfusion, the INR decreased to ⬍1.5 in only 1 patient. Four patients with a platelet count ⬍40,000/ mm3 received platelet transfusions. Three patients received a packed red blood cell infusion. In each case, the anemia was attributed to gastrointestinal bleeding. Discussion In the present study, we sought to find an association between INR and bleeding associated with cardiac catheterization in patients with ELSD and found none. Our data suggest that a moderately elevated INR poses no risk with invasive procedures in patients with ESLD despite the concern frequently expressed by those who perform such procedures. Even when our patients were dichotomized into normal and elevated INR groups, no significant difference in procedural complications was identified. This is especially important because one of the greatest reported reasons for blood product administration is the correction of an elevated INR in preparation for an invasive procedure.5 Historically, an elevated prothrombin time and its derived INR have been used to predict bleeding from invasive procedures. Although these laboratory variables are associated with an increased risk of hemorrhage in patients treated with warfarin-type anticoagulants, their utility and ability to predict bleeding in patients with cirrhosis is unclear.6,7 Patients with ESLD, because of their impaired hepatic syn-
thetic function, have a characteristic coagulation profile that is now referred to as “rebalanced hemostasis.”8 Hepatic production of both procoagulant (factors II, VII, IX, X) and anticoagulant (protein C, protein S, antithrombin) factors is reduced.7 This resets the hemostatic balance despite an increase in the prothrombin time/INR. Continued understanding of the complex interplay between those factors that promote and those that impair hemostasis has cast doubt on whether the prothrombin time/INR is predictive of bleeding risk in patients with ESLD or merely serves as a marker of hepatic synthetic impairment.7 Our findings are in accordance with the results of several published studies.9 Segal and Dzik,10 in a large systematic review of studies involving patients with an elevated prothrombin time or INR, did not find a significant increase in bleeding, although not all the studies they reviewed included patients with ESLD. One study included in their review is worth highlighting. In that prospective investigation of patients with ESLD undergoing central venous access placement, only 1 major bleeding complication was observed, and this was in a patient with an INR of 1.5. When comparing patients with an INR ⬎5 and ⬍5, the only statistically significant different finding was for superficial hematomas, which were found in 12.4% of those with an INR ⬎5 and in only 5.6% of those with an INR ⬍5.11 Not only do these published results suggest that the INR might not accurately predict those at high risk of bleeding, but also little evidence is available to suggest that the correction of INR by administration of FFP has any beneficial clinical effect.12,13 Thus, the potential risk and significant cost associated with blood product transfusion could be avoided in this patient population. Bleeding complications with invasive procedures can still occur in patients with ESLD—just as they can in patients without ESLD— but when they do, the INR elevation is not likely to be the cause. Several limitations were inherent to our retrospective study in which only major bleeding and vascular events were likely to have been recorded, and small hematomas or increased bruising might have been missed or not consid-
Miscellaneous/Cardiac Catheterization in Patients With Coagulopathy
ered clinically significant enough to have been reported. Undoubtedly, the possibility of selection bias was present such that those considered most at risk of procedural complications did not undergo catheterization. It could also be that the operating physicians, aware of the elevated INR levels, took extra care to avoid bleeding complications. Despite a patient population with an elevated INR, high model for ESLD scores, renal dysfunction, and thrombocytopenia, we did not identify any serious catheter-related complications, nor could we find any association between INR and bleeding risk. Our conclusion, inferred from the present findings and the results of published studies, is that the correction of INR with FFP, which puts the patients at risk of volume overload and transfusion-related acute lung injury,14 to reduce a theoretical risk of catheterization-related bleeding owing to INR elevation, is unnecessary. These results should be confirmed prospectively and include patients with ESLD and greater INR levels than seen in our population. 1. Vaitkus PT, Dickens C, McGrath MK. Low bleeding risk from cardiac catheterization in patients with advanced liver disease. Catheter Cardiovasc Interv 2005;65:510 –512. 2. Pillarisetti J, Patel P, Duthuluru S, Roberts J, Chen W, Genton R, Wiley M, Candipan R, Tadros P, Gupta K. Cardiac catheterization in patients with end-stage liver disease: safety and outcomes. Catheter Cardiovasc Interv 2011;77:45– 48. 3. Sharma M, Yong C, Majure D, Zellner C, Roberts JP, Bass NM, Ports TA, Yeghiazarians Y, Gregoratos G, Boyle AJ. Safety of cardiac catheterization in patients with end-stage liver disease awaiting liver transplantation. Am J Cardiol 2009;103:742–746. 4. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing tran-
5. 6.
7. 8. 9.
10.
11.
12.
13.
14.
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sjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864 – 871. Dzik W, Rao A. Why do physicians request fresh frozen plasma? Transfusion 2004;44:1393–1394. Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association, American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107:1692–1711. Roberts LN, Patel RK, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol 2010;148:507–521. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010;116:878 – 885. Malloy PC, Grassi CJ, Kundu S, Gervais DA, Miller DL, Osnis RB, Postoak DW, Rajan DK, Sacks D, Schwartzberg MS, Zuckerman DA, Cardella JF; Standards of Practice Committee with Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Endorsement. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol 2009;20:S240 –S249. Segal JB, Dzik WH; Transfusion Medicine/Hemostasis Clinical Trials Network. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005;45:1413–1425. Fisher NC, Mutimer DJ. Central venous cannulation in patients with liver disease and coagulopathy—a prospective audit. Intensive Care Med 1999;25:481– 485. Youssef WI, Salazar F, Dasarathy S, Beddow T, Mullen KD. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol 2003;98:1391–1394. Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;126:139 –152. Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore SB, Hubmayr RD, Gajic O. Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007;131:1308 –1314.